IMMORTALIZATION OF HUMAN-CELLS AND LAS MECHANISMS

One of the contributions of in vitro neoplastic transformation studies on human cells is the confirmation that cells become malignant by a m ultistep process. In this review, we use the term ''neoplastic transfo rmation'' to indicate that the cells become capable of forming a histo logically malignant tumor, that is, one that invades and/or erodes nor mal tissue and is serially transplantable in a susceptible animal host . Phenotypically, the cells first become immortalized and then neoplas tic. If normal human cells do not overcome aging by becoming immortali zed, they cannot be neoplastically transformed. However, normal human cells are stringently destined to cellular aging and very rarely becom e immortalized by oncogenic DNA viruses (SV40, papillomavirus types 16 and 18, adenovirus types 5 and 12), chemicals, X-rays, or spontaneous ly. Once human cells get immortalized, they relatively easily become n eoplastic. Evidence shows that immortalization is a critical step in t he neoplastic transformation process of human cells. Therefore, invest igation of the mechanisms of immortalization is indispensable in under standing the multistep carcinogenesis of human cells. Although the pre cise mechanisms of immortalization are unknown at present, data indica te that the p53 cascade appears to be important for the immortalizatio n of human cells. The loss of functions of normal p53 may induce genom ic instability, resulting in mutations of some other unknown genes tha t are more directly involved in the immortalization of human cells. Th ese unknown genes, which are presumably located at chromosomes 1, 4, 6 , 7, 9, 11, 13, 17, 18, and X are now under extensive investigation.